OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have cardiovascular benefits, but whether this is via metabolic improvements or direct effect remains controversial. This study aimed to explore the causal link between GLP-1RAs and myocardial infarction (MI) and quantify the contribution of metabolic improvements. RESEARCH DESIGN AND METHODS Mendelian randomization (MR) was applied to assess the causal relationship between GLP-1RAs and MI, and two-step MR analysis was applied to quantify the mediating role of metabolic traits. The direct effect of GLP-1RAs on MI was evaluated by multivariate Mendelian randomization (MVMR). Genetic variants associated with GLP-1 receptor (GLP-1R) expression (proxying GLP-1RAs) were used as instrumental variables. Genome-wide association studies (GWAS) data for metabolic traits glycated hemoglobin (HbA1c), BMI, lipid profile, and blood pressure were sourced from the Million Veteran Program, serving as mediators. GWAS data for type 2 diabetes mellitus (T2DM) were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, and data for MI were sourced from the UK Biobank/Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus The Coronary Artery Disease (CARDIoGRAMplusC4D), serving as outcomes. All GWAS data were restricted to European ancestry. RESULTS Higher GLP-1R expression was correlated with a lower risk of T2DM (odds ratio 0.94 [95% CI 0.92, 0.97]) and MI (0.97 [0.95, 1.00]). Metabolic improvements mediated this association: HbA1c (36.67% [3.89, 69.44]), BMI (28.86% [2.62, 55.10]), triglycerides (18.52% [1.47, 35.57]), HDL-cholesterol (18.28% [1.45, 35.12]), and systolic blood pressure (11.55% [0.33, 22.76]). No direct effect of GLP-1R expression on MI was observed after adjusting for metabolic traits (β = −0.003, P = 0.12). CONCLUSIONS GLP-1RAs protect against MI primarily through metabolic improvements, with no direct effect independent of these pathways. These findings support prioritizing metabolic improvements to reduce cardiovascular risk with GLP-1RAs.
胰高血糖素样肽-1受体激动剂（GLP-1RAs）具有心血管益处，但这是通过代谢改善还是直接作用仍存在争议。本研究旨在探讨GLP-1RAs与心肌梗死（MI）之间的因果关系，并量化代谢改善的贡献。研究设计与方法采用孟德尔随机化（Mendelian randomization， MR）评估GLP-1RAs与心肌梗死之间的因果关系，采用两步MR分析量化代谢性状的中介作用。通过多变量孟德尔随机化（MVMR）评估GLP-1RAs对心肌梗死的直接影响。与GLP-1受体（GLP-1R）表达相关的遗传变异（代理GLP-1RAs）被用作工具变量。代谢特征糖化血红蛋白（HbA1c）、BMI、脂质谱和血压的全基因组关联研究（GWAS）数据来自百万退伍军人计划，作为中介。2型糖尿病（T2DM）的GWAS数据来自糖尿病遗传学复制和荟萃分析（图）联盟，心肌梗死的数据来自英国生物银行/冠状动脉疾病基因组广泛复制和荟萃分析加上冠状动脉疾病（CARDIoGRAMplusC4D），作为结局。所有GWAS数据仅限于欧洲血统。结果较高的GLP-1R表达与较低的T2DM（优势比0.94 [95% CI 0.92, 0.97]）和心肌梗死（优势比0.97[0.95,1.00]）风险相关。代谢改善介导了这种关联：HbA1c（36.67%[3.89, 69.44]）、BMI（28.86%[2.62, 55.10]）、甘油三酯（18.52%[1.47,35.57]）、高密度脂蛋白胆固醇（18.28%[1.45,35.12]）和收缩压（11.55%[0.33,22.76]）。调整代谢性状后，GLP-1R表达对心肌梗死无直接影响（β = - 0.003, P = 0.12）。结论：GLP-1RAs主要通过代谢改善来预防心肌梗死，没有独立于这些途径的直接作用。这些发现支持GLP-1RAs优先改善代谢以降低心血管风险。
{"title":"Metabolic Improvement Mediates the Causal Relationship Between GLP-1 Receptor Agonists and Myocardial Infarction: A Mendelian Randomization and Mediation Analysis Study","authors":"Jingkai Tong, Nana Li, Fang Hu, Yingying Yue","doi":"10.2337/dc25-1822","DOIUrl":"https://doi.org/10.2337/dc25-1822","url":null,"abstract":"OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have cardiovascular benefits, but whether this is via metabolic improvements or direct effect remains controversial. This study aimed to explore the causal link between GLP-1RAs and myocardial infarction (MI) and quantify the contribution of metabolic improvements. RESEARCH DESIGN AND METHODS Mendelian randomization (MR) was applied to assess the causal relationship between GLP-1RAs and MI, and two-step MR analysis was applied to quantify the mediating role of metabolic traits. The direct effect of GLP-1RAs on MI was evaluated by multivariate Mendelian randomization (MVMR). Genetic variants associated with GLP-1 receptor (GLP-1R) expression (proxying GLP-1RAs) were used as instrumental variables. Genome-wide association studies (GWAS) data for metabolic traits glycated hemoglobin (HbA1c), BMI, lipid profile, and blood pressure were sourced from the Million Veteran Program, serving as mediators. GWAS data for type 2 diabetes mellitus (T2DM) were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, and data for MI were sourced from the UK Biobank/Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus The Coronary Artery Disease (CARDIoGRAMplusC4D), serving as outcomes. All GWAS data were restricted to European ancestry. RESULTS Higher GLP-1R expression was correlated with a lower risk of T2DM (odds ratio 0.94 [95% CI 0.92, 0.97]) and MI (0.97 [0.95, 1.00]). Metabolic improvements mediated this association: HbA1c (36.67% [3.89, 69.44]), BMI (28.86% [2.62, 55.10]), triglycerides (18.52% [1.47, 35.57]), HDL-cholesterol (18.28% [1.45, 35.12]), and systolic blood pressure (11.55% [0.33, 22.76]). No direct effect of GLP-1R expression on MI was observed after adjusting for metabolic traits (β = −0.003, P = 0.12). CONCLUSIONS GLP-1RAs protect against MI primarily through metabolic improvements, with no direct effect independent of these pathways. These findings support prioritizing metabolic improvements to reduce cardiovascular risk with GLP-1RAs.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"30 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An Ran Ran, Jennifer Li Ding, Ziqi Tang, Ching Lam, Truong X. Nguyen, Jiaying Zhou, Shuyi Zhang, Danqi Fang, Dawei Yang, Vincent Ng, Duoru Lin, Haotian Lin, Clement C. Tham, Carmen K.M. Chan, Simon K.H. Szeto, Tien Y. Wong, Sobha Sivaprasad, Carol Y. Cheung
Background Deep learning (DL) has shown promise in delivering diagnostic and economic benefits for detecting diabetic retinopathy (DR) from fundus photographs (FPs). However, evidence synthesis of model validation in prospective, real-world settings remains limited. Purpose To assess the feasibility of implementing DL-DR systems using FPs across different countries by synthesizing prospective validation and economic evidence. Data Sources Five databases were searched until 13 August 2025. Study Selection Studies prospectively assessing diagnostic performance and/or studies conducting economic analyses of DL-DR systems using FPs were selected. Data Extraction Characteristics of all studies, performance parameters of prospective validation studies, and economic outcomes of economic analysis studies were extracted. Data Synthesis Forty-seven studies were included in the meta-analysis. The pooled performance was the highest in detecting vision-threatening DR (area under the receiver operating characteristic curve [AUROC] 0.974), followed by any DR (AUROC 0.965), then referable DR (RDR) (AUROC 0.959). Study region, clinical pathway, mydriasis, image quality control, sample size, grading criteria, reference standard, and model architecture significantly affected model performance in RDR detection. Fifteen studies were included in the economic commentary, showing that DL-based DR screening was cost-effective in high-income countries, whereas results in middle-income countries were mixed, depending on compliance rates, glycemic control, and initial costs. Limitations A paucity of studies assessing multiple severities of DR or diabetic macular edema restricted our ability to perform subgroup analyses. Insights into low-income countries were limited by a lack of studies in these regions. Conclusions DL-DR systems using FPs had high discriminative performance in prospective real-world settings and hold promise to improve cost-effectiveness, especially in high-income countries.
{"title":"Real-World Prospective Validation and Economic Evaluation of Deep Learning-Based Diabetic Retinopathy Detection From Fundus Photographs: A Systematic Review and Meta-analysis","authors":"An Ran Ran, Jennifer Li Ding, Ziqi Tang, Ching Lam, Truong X. Nguyen, Jiaying Zhou, Shuyi Zhang, Danqi Fang, Dawei Yang, Vincent Ng, Duoru Lin, Haotian Lin, Clement C. Tham, Carmen K.M. Chan, Simon K.H. Szeto, Tien Y. Wong, Sobha Sivaprasad, Carol Y. Cheung","doi":"10.2337/dc25-1493","DOIUrl":"https://doi.org/10.2337/dc25-1493","url":null,"abstract":"Background Deep learning (DL) has shown promise in delivering diagnostic and economic benefits for detecting diabetic retinopathy (DR) from fundus photographs (FPs). However, evidence synthesis of model validation in prospective, real-world settings remains limited. Purpose To assess the feasibility of implementing DL-DR systems using FPs across different countries by synthesizing prospective validation and economic evidence. Data Sources Five databases were searched until 13 August 2025. Study Selection Studies prospectively assessing diagnostic performance and/or studies conducting economic analyses of DL-DR systems using FPs were selected. Data Extraction Characteristics of all studies, performance parameters of prospective validation studies, and economic outcomes of economic analysis studies were extracted. Data Synthesis Forty-seven studies were included in the meta-analysis. The pooled performance was the highest in detecting vision-threatening DR (area under the receiver operating characteristic curve [AUROC] 0.974), followed by any DR (AUROC 0.965), then referable DR (RDR) (AUROC 0.959). Study region, clinical pathway, mydriasis, image quality control, sample size, grading criteria, reference standard, and model architecture significantly affected model performance in RDR detection. Fifteen studies were included in the economic commentary, showing that DL-based DR screening was cost-effective in high-income countries, whereas results in middle-income countries were mixed, depending on compliance rates, glycemic control, and initial costs. Limitations A paucity of studies assessing multiple severities of DR or diabetic macular edema restricted our ability to perform subgroup analyses. Insights into low-income countries were limited by a lack of studies in these regions. Conclusions DL-DR systems using FPs had high discriminative performance in prospective real-world settings and hold promise to improve cost-effectiveness, especially in high-income countries.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"29 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Edith W. K. Chow, Yingnan Fan, Hongjiang Wu, Eric S. H. Lau, Aimin Yang, Elaine Chow, Alice P. S. Kong, Ronald C. W. Ma, Juliana C. N. Chan, Andrea O. Y. Luk
OBJECTIVE The impact of young-onset hypertension (YOH) on cardiovascular and kidney outcomes in people with type 2 diabetes (T2D) has not been systematically studied. RESEARCH DESIGN AND METHODS This is a retrospective cohort study. We identified individuals with T2D and hypertension who underwent diabetes assessment between 2010 and 2024 in Hong Kong. We defined YOH as hypertension presenting at age <45 years. Individuals with YOH and late-onset hypertension (LOH) were compared with individuals with T2D without hypertension matched for age, sex, diabetes duration, and calendar year. Cox regression was conducted to derive hazard ratios (HRs) and 95% CIs for cardiovascular disease, chronic kidney disease, end-stage kidney disease, and all-cause death in YOH and LOH groups compared with their respective matched control groups. Risk modification by sex was explored in a subgroup analysis. RESULTS A total of 19,224 individuals with YOH and 57,795 individuals with LOH were matched with respective control individuals. YOH was associated with a greater increase in risks for cardiovascular disease (HR 1.83 [95% CI 1.65, 2.03] vs. 1.43 [1.36, 1.5] for LOH), chronic kidney disease (2.58 [2.38, 2.8] vs. 1.81 [1.75, 1.88] for LOH), congestive heart failure (2.58 [1.92, 3.47] vs. 1.81 [1.61, 2.03] for LOH), and death (1.37 [1.22, 1.54] vs. 1.31 [1.25, 1.37] for LOH) (P for interaction < 0.01). Differences in excess risks between YOH and LOH were more pronounced in women than men for cardiovascular disease and coronary heart disease (P for three-way interaction < 0.05). CONCLUSIONS YOH conferred greater risks of cardiovascular and kidney outcomes than LOH in T2D.
目的：年轻发病高血压（YOH）对2型糖尿病（T2D）患者心血管和肾脏预后的影响尚未系统研究。研究设计与方法：回顾性队列研究。我们确定了2010年至2024年间在香港接受糖尿病评估的T2D和高血压患者。我们将YOH定义为出现在年龄&；lt；45年。将YOH合并迟发性高血压（LOH）患者与不伴有高血压的T2D患者进行年龄、性别、糖尿病病程和日历年匹配的比较。进行Cox回归，得出YOH和LOH组与相应对照组相比心血管疾病、慢性肾脏疾病、终末期肾脏疾病和全因死亡的风险比（hr）和95% ci。在亚组分析中探讨了性别对风险的影响。结果YOH患者共19,224例，LOH患者共57,795例。YOH与心血管疾病（LOH的危险度为1.83 [95% CI 1.65, 2.03]比1.43[1.36,1.5]）、慢性肾脏疾病（LOH的危险度为2.58[2.38,2.8]比1.81[1.75,1.88]）、充血性心力衰竭（LOH的危险度为2.58[1.92,3.47]比1.81[1.61,2.03]）和死亡（LOH的危险度为1.37[1.22,1.54]比1.31[1.25,1.37]）相关（P为相互作用& lt； 0.01）。女性患心血管疾病和冠心病的风险在YOH和LOH之间的差异比男性更明显（P为三向相互作用&；lt; 0.05）。结论：与LOH相比，YOH在T2D中具有更大的心血管和肾脏预后风险。
{"title":"Young-Onset Hypertension Confers Higher Risk of Cardiovascular Disease, Kidney Disease, and All-Cause Mortality in Individuals With Type 2 Diabetes: A Propensity Score–Matched Cohort Analysis","authors":"Edith W. K. Chow, Yingnan Fan, Hongjiang Wu, Eric S. H. Lau, Aimin Yang, Elaine Chow, Alice P. S. Kong, Ronald C. W. Ma, Juliana C. N. Chan, Andrea O. Y. Luk","doi":"10.2337/dc25-1839","DOIUrl":"https://doi.org/10.2337/dc25-1839","url":null,"abstract":"OBJECTIVE The impact of young-onset hypertension (YOH) on cardiovascular and kidney outcomes in people with type 2 diabetes (T2D) has not been systematically studied. RESEARCH DESIGN AND METHODS This is a retrospective cohort study. We identified individuals with T2D and hypertension who underwent diabetes assessment between 2010 and 2024 in Hong Kong. We defined YOH as hypertension presenting at age &lt;45 years. Individuals with YOH and late-onset hypertension (LOH) were compared with individuals with T2D without hypertension matched for age, sex, diabetes duration, and calendar year. Cox regression was conducted to derive hazard ratios (HRs) and 95% CIs for cardiovascular disease, chronic kidney disease, end-stage kidney disease, and all-cause death in YOH and LOH groups compared with their respective matched control groups. Risk modification by sex was explored in a subgroup analysis. RESULTS A total of 19,224 individuals with YOH and 57,795 individuals with LOH were matched with respective control individuals. YOH was associated with a greater increase in risks for cardiovascular disease (HR 1.83 [95% CI 1.65, 2.03] vs. 1.43 [1.36, 1.5] for LOH), chronic kidney disease (2.58 [2.38, 2.8] vs. 1.81 [1.75, 1.88] for LOH), congestive heart failure (2.58 [1.92, 3.47] vs. 1.81 [1.61, 2.03] for LOH), and death (1.37 [1.22, 1.54] vs. 1.31 [1.25, 1.37] for LOH) (P for interaction &lt; 0.01). Differences in excess risks between YOH and LOH were more pronounced in women than men for cardiovascular disease and coronary heart disease (P for three-way interaction &lt; 0.05). CONCLUSIONS YOH conferred greater risks of cardiovascular and kidney outcomes than LOH in T2D.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"72 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vera Lehmann, Martin Hilpert, Zohreh Mostaani, Sevada Hovsepyan, Esmé Wallace, Colombine Verzat, Stefan Feuerriegel, Mathias Kraus, James Rosenthal, Gürkan Yilmaz, Mathew Magimai Doss, Christoph Stettler
OBJECTIVE Hypoglycemia is a hazardous diabetes-related emergency. We aimed to develop a machine learning (ML) approach for noninvasive hypoglycemia detection using voice data. RESEARCH DESIGN AND METHODS We collected voice data (540 recordings) with a smartphone in standardized euglycemia and hypoglycemia in two sequential clinical studies in people with type 1 diabetes. Using these data, we trained and evaluated an ML approach to detect hypoglycemia solely based on voice features. RESULTS Twenty-two individuals were included (11 female, age 37.3 ± 12.4 years, HbA1c 7.1 ± 0.5%). The ML approach detected hypoglycemia noninvasively with high accuracy (area under the receiver operating characteristic curve 0.90 ± 0.12 for reading a text aloud and 0.87 ± 0.15 for rapid repetition of syllables [diadochokinetic task]). CONCLUSIONS An ML approach exclusively based on voice data allows for noninvasive hypoglycemia detection, corroborating the potential of ML-based approaches to infer acute health states through voice.
{"title":"Listening to Hypoglycemia: Voice as a Biomarker for Detection of a Medical Emergency Using Machine Learning","authors":"Vera Lehmann, Martin Hilpert, Zohreh Mostaani, Sevada Hovsepyan, Esmé Wallace, Colombine Verzat, Stefan Feuerriegel, Mathias Kraus, James Rosenthal, Gürkan Yilmaz, Mathew Magimai Doss, Christoph Stettler","doi":"10.2337/dc25-1680","DOIUrl":"https://doi.org/10.2337/dc25-1680","url":null,"abstract":"OBJECTIVE Hypoglycemia is a hazardous diabetes-related emergency. We aimed to develop a machine learning (ML) approach for noninvasive hypoglycemia detection using voice data. RESEARCH DESIGN AND METHODS We collected voice data (540 recordings) with a smartphone in standardized euglycemia and hypoglycemia in two sequential clinical studies in people with type 1 diabetes. Using these data, we trained and evaluated an ML approach to detect hypoglycemia solely based on voice features. RESULTS Twenty-two individuals were included (11 female, age 37.3 ± 12.4 years, HbA1c 7.1 ± 0.5%). The ML approach detected hypoglycemia noninvasively with high accuracy (area under the receiver operating characteristic curve 0.90 ± 0.12 for reading a text aloud and 0.87 ± 0.15 for rapid repetition of syllables [diadochokinetic task]). CONCLUSIONS An ML approach exclusively based on voice data allows for noninvasive hypoglycemia detection, corroborating the potential of ML-based approaches to infer acute health states through voice.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"5 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Type 2 diabetes has traditionally been viewed as a chronic, progressive condition. However, recent innovations, such as accessible low-calorie diets and newer weight loss medications, are challenging this paradigm. Evidence from clinical trials and mechanistic studies indicates that intentional weight loss, especially early in the disease course, can meaningfully alter its trajectory through reducing ectopic fat and glycemic levels. New medications that reduce “food noise” are particularly valuable in today’s obesogenic environments, helping patients regain some control over calorie intake and supporting sustainable lifestyle changes. These therapies can lead to weight loss of ≥10% in type 2 diabetes and may enable newly diagnosed individuals to achieve and maintain normoglycemia for many years. Early, substantial weight loss combined with glycemic normalization has the potential to extend life expectancy, reduce or delay complications associated with obesity and hyperglycemia, improve quality of life, and lower long-term care needs. Beyond weight reduction, additional health benefits are offered by these medications, as they also slow atherosclerosis and preserve kidney function. Building on recent American Diabetes Association–European Association for the Study of Diabetes guideline recommendations, we propose that intentional weight loss at or near the time of diagnosis be considered a central strategy in type 2 diabetes management. To support this shift, proof-of-concept trials should be conducted for assessment of the long-term efficacy and durability of this approach. With success, increased competition and broader access to weight loss medications could lower costs and expand availability—even in low- and middle-income countries, where diabetes rates are rising rapidly—supporting a transformative change in the global standard of care.
{"title":"Why Early, Large-scale Weight Loss Is the Future of Type 2 Diabetes Care","authors":"Naveed Sattar, John B. Buse","doi":"10.2337/dci25-0069","DOIUrl":"https://doi.org/10.2337/dci25-0069","url":null,"abstract":"Type 2 diabetes has traditionally been viewed as a chronic, progressive condition. However, recent innovations, such as accessible low-calorie diets and newer weight loss medications, are challenging this paradigm. Evidence from clinical trials and mechanistic studies indicates that intentional weight loss, especially early in the disease course, can meaningfully alter its trajectory through reducing ectopic fat and glycemic levels. New medications that reduce “food noise” are particularly valuable in today’s obesogenic environments, helping patients regain some control over calorie intake and supporting sustainable lifestyle changes. These therapies can lead to weight loss of ≥10% in type 2 diabetes and may enable newly diagnosed individuals to achieve and maintain normoglycemia for many years. Early, substantial weight loss combined with glycemic normalization has the potential to extend life expectancy, reduce or delay complications associated with obesity and hyperglycemia, improve quality of life, and lower long-term care needs. Beyond weight reduction, additional health benefits are offered by these medications, as they also slow atherosclerosis and preserve kidney function. Building on recent American Diabetes Association–European Association for the Study of Diabetes guideline recommendations, we propose that intentional weight loss at or near the time of diagnosis be considered a central strategy in type 2 diabetes management. To support this shift, proof-of-concept trials should be conducted for assessment of the long-term efficacy and durability of this approach. With success, increased competition and broader access to weight loss medications could lower costs and expand availability—even in low- and middle-income countries, where diabetes rates are rising rapidly—supporting a transformative change in the global standard of care.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"144 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peipei Liu, Jiaxi Yang, Dong Hoon Lee, Ling-Jun Li, Wei Wei Pang, Jorge E. Chavarro, Frank B. Hu, Cuilin Zhang
OBJECTIVE We examined the associations of inflammatory and insulinemic diets with type 2 diabetes (T2D) risk among women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We followed 4,318 women with a history of GDM in the Nurses’ Health Study II for incident T2D between 1991 and 2019. Empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores were calculated using prevalidated methods. Cox models were used to calculate hazard ratios (HRs) and 95% CIs for the risk of T2D. Additionally, we estimated the least squares means of cardiometabolic biomarkers according to EDIP and EDIH quintiles in a subset of participants who were free of T2D at the time of blood collection. RESULTS During 84,174 person-years of follow-up, 1,037 women developed T2D. After adjusting for major covariates, including BMI, higher EDIP and EDIH scores, which indicated greater dietary inflammatory and insulinemic potential, were associated with an increased risk of T2D. Compared with those for the lowest quintile, adjusted HRs (95% CIs) for the highest quintile were 1.32 (1.06, 1.64) for EDIP and 1.44 (1.14, 1.82) for EDIH (both Ptrend < 0.05). Higher EDIP scores were significantly associated with higher concentrations of insulin and lower levels of HDL cholesterol, and EDIH scores were significantly positively associated with insulin and C-peptide concentrations. CONCLUSIONS Among women with a history of GDM, those with greater dietary inflammatory and insulinemic potential were found to be at a higher risk of T2D and to have unfavorable cardiometabolic profiles.
{"title":"Inflammatory and Insulinemic Dietary Patterns and Risk of Type 2 Diabetes Among Women With a History of Gestational Diabetes Mellitus: A Prospective Study of 84,174 Person-Years of Follow-up","authors":"Peipei Liu, Jiaxi Yang, Dong Hoon Lee, Ling-Jun Li, Wei Wei Pang, Jorge E. Chavarro, Frank B. Hu, Cuilin Zhang","doi":"10.2337/dc25-1919","DOIUrl":"https://doi.org/10.2337/dc25-1919","url":null,"abstract":"OBJECTIVE We examined the associations of inflammatory and insulinemic diets with type 2 diabetes (T2D) risk among women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We followed 4,318 women with a history of GDM in the Nurses’ Health Study II for incident T2D between 1991 and 2019. Empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores were calculated using prevalidated methods. Cox models were used to calculate hazard ratios (HRs) and 95% CIs for the risk of T2D. Additionally, we estimated the least squares means of cardiometabolic biomarkers according to EDIP and EDIH quintiles in a subset of participants who were free of T2D at the time of blood collection. RESULTS During 84,174 person-years of follow-up, 1,037 women developed T2D. After adjusting for major covariates, including BMI, higher EDIP and EDIH scores, which indicated greater dietary inflammatory and insulinemic potential, were associated with an increased risk of T2D. Compared with those for the lowest quintile, adjusted HRs (95% CIs) for the highest quintile were 1.32 (1.06, 1.64) for EDIP and 1.44 (1.14, 1.82) for EDIH (both Ptrend &lt; 0.05). Higher EDIP scores were significantly associated with higher concentrations of insulin and lower levels of HDL cholesterol, and EDIH scores were significantly positively associated with insulin and C-peptide concentrations. CONCLUSIONS Among women with a history of GDM, those with greater dietary inflammatory and insulinemic potential were found to be at a higher risk of T2D and to have unfavorable cardiometabolic profiles.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"27 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raymond J. Kreienkamp, Kirk Smith, Thinley Yidzin Wangden, Aaron J. Deutsch, Steven D. Gage, Anna Bellatorre, Dana M. Dabelea, Ralph B. D’Agostino, Lawrence M. Dolan, Jose C. Florez, Elizabeth T. Jensen, Catherine Pihoker, Toni I. Pollin, Amy S. Shah, Lukasz Szczerbinski, Miriam S. Udler, Shylaja Srinivasan
OBJECTIVE Clinical heterogeneity in youth-onset type 2 diabetes is less understood than that of adult-onset type 2 diabetes. We performed phenotypic clustering of youth-onset type 2 diabetes to determine whether clusters provided clinical utility. RESEARCH DESIGN AND METHODS We performed data-driven clustering in a diverse subset of autoantibody-negative, clinician-diagnosed type 2 diabetes before age 20 years in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) (n = 525) and the SEARCH for Diabetes in Youth (SEARCH) (n = 333) studies. Participants were clustered using 1) similar variables as previously described in adults and 2) novel routinely available clinical variables. We assessed the effectiveness of the clusters, as well as that of simple clinical measures, to predict treatment response in the TODAY clinical trial. RESULTS There were three youth-onset type 2 diabetes clusters: 1) youth-onset insulin-deficient diabetes (YIDD-T2), 2) youth-onset insulin-resistant diabetes, and 3) intermediate youth-onset diabetes. These clusters had differential responses to therapies and risk of treatment failure in the TODAY study, with those in the YIDD-T2 cluster experiencing the highest rate of treatment failure, regardless of treatment arm. YIDD-T2 also had high rates of type 2 diabetes complications. We then generated three novel clusters, with different rates of treatment failure, using variables available in routine clinical practice. Compared with both clustering methods, simple clinical measures performed comparably or better at predicting treatment response and complications. CONCLUSIONS Youth-onset type 2 diabetes can be characterized into reproducible clusters that demonstrate differential response to treatments and risk of complications. Nevertheless, cluster membership did not add clinical utility beyond simple clinical measures for predicting outcomes.
{"title":"Novel Phenotypic Clusters of Youth-Onset Type 2 Diabetes Offer No Added Prognostic Value to Simple Clinical Measures","authors":"Raymond J. Kreienkamp, Kirk Smith, Thinley Yidzin Wangden, Aaron J. Deutsch, Steven D. Gage, Anna Bellatorre, Dana M. Dabelea, Ralph B. D’Agostino, Lawrence M. Dolan, Jose C. Florez, Elizabeth T. Jensen, Catherine Pihoker, Toni I. Pollin, Amy S. Shah, Lukasz Szczerbinski, Miriam S. Udler, Shylaja Srinivasan","doi":"10.2337/dc25-1765","DOIUrl":"https://doi.org/10.2337/dc25-1765","url":null,"abstract":"OBJECTIVE Clinical heterogeneity in youth-onset type 2 diabetes is less understood than that of adult-onset type 2 diabetes. We performed phenotypic clustering of youth-onset type 2 diabetes to determine whether clusters provided clinical utility. RESEARCH DESIGN AND METHODS We performed data-driven clustering in a diverse subset of autoantibody-negative, clinician-diagnosed type 2 diabetes before age 20 years in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) (n = 525) and the SEARCH for Diabetes in Youth (SEARCH) (n = 333) studies. Participants were clustered using 1) similar variables as previously described in adults and 2) novel routinely available clinical variables. We assessed the effectiveness of the clusters, as well as that of simple clinical measures, to predict treatment response in the TODAY clinical trial. RESULTS There were three youth-onset type 2 diabetes clusters: 1) youth-onset insulin-deficient diabetes (YIDD-T2), 2) youth-onset insulin-resistant diabetes, and 3) intermediate youth-onset diabetes. These clusters had differential responses to therapies and risk of treatment failure in the TODAY study, with those in the YIDD-T2 cluster experiencing the highest rate of treatment failure, regardless of treatment arm. YIDD-T2 also had high rates of type 2 diabetes complications. We then generated three novel clusters, with different rates of treatment failure, using variables available in routine clinical practice. Compared with both clustering methods, simple clinical measures performed comparably or better at predicting treatment response and complications. CONCLUSIONS Youth-onset type 2 diabetes can be characterized into reproducible clusters that demonstrate differential response to treatments and risk of complications. Nevertheless, cluster membership did not add clinical utility beyond simple clinical measures for predicting outcomes.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"18 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chan Mi Park, Saran Thanapluetiwong, Xiecheng Chen, Gahee Oh, Darae Ko, Dae Hyun Kim
OBJECTIVE Older adults with type 2 diabetes are at high risk for frailty. The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on frailty remain uncertain. RESEARCH DESIGN AND METHODS Using a 7% random sample of Medicare data, we compared new users of dipeptidyl peptidase-4 inhibitors (DPP-4is), GLP-1RAs, SGLT-2is, and sulfonylureas on 1-year frailty progression, measured by a claims-based frailty index (CFI) (range: 0–1; higher scores indicate greater frailty). Mediation analyses assessed whether cardiovascular or safety events explained differences in frailty progression. RESULTS Compared with DPP-4i users, the mean CFI change (95% CI) was significantly lower for GLP-1RA (−0.007 [−0.011, −0.004]) and SGLT-2i (−0.005 [−0.008, −0.002]) users; no difference was found for sulfonylurea users. These associations were minimally mediated by cardiovascular or safety events. CONCLUSIONS GLP-1RAs and SGLT-2is may slow frailty progression through mechanisms independent of cardiovascular benefits. Future trials should confirm these preliminary findings.
{"title":"Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Frailty Progression in Older Adults With Type 2 Diabetes","authors":"Chan Mi Park, Saran Thanapluetiwong, Xiecheng Chen, Gahee Oh, Darae Ko, Dae Hyun Kim","doi":"10.2337/dc25-1031","DOIUrl":"https://doi.org/10.2337/dc25-1031","url":null,"abstract":"OBJECTIVE Older adults with type 2 diabetes are at high risk for frailty. The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on frailty remain uncertain. RESEARCH DESIGN AND METHODS Using a 7% random sample of Medicare data, we compared new users of dipeptidyl peptidase-4 inhibitors (DPP-4is), GLP-1RAs, SGLT-2is, and sulfonylureas on 1-year frailty progression, measured by a claims-based frailty index (CFI) (range: 0–1; higher scores indicate greater frailty). Mediation analyses assessed whether cardiovascular or safety events explained differences in frailty progression. RESULTS Compared with DPP-4i users, the mean CFI change (95% CI) was significantly lower for GLP-1RA (−0.007 [−0.011, −0.004]) and SGLT-2i (−0.005 [−0.008, −0.002]) users; no difference was found for sulfonylurea users. These associations were minimally mediated by cardiovascular or safety events. CONCLUSIONS GLP-1RAs and SGLT-2is may slow frailty progression through mechanisms independent of cardiovascular benefits. Future trials should confirm these preliminary findings.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"115 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dustin Le, Mark Kilpatrick, Walter K. Kraft, Morgan E. Grams, Bernard G. Jaar, Jung-Im Shin
OBJECTIVE Glucagon-like peptide 1 agonists (GLP-1s) compared with dipeptidyl peptidase 4 inhibitors (DPP-4s) are associated with reduced risk of dementia in the general population with diabetes, but whether this association is true for patients requiring hemodialysis is unknown. RESEARCH DESIGN AND METHODS Using the U.S. Renal Data System and Medicare Parts A, B, and D claims data from 2011 to 2021, we used the active comparator, new-user design to evaluate incident dementia comparing GLP-1s versus DPP-4s among individuals with both diabetes and hemodialysis dependence. We used inverse probability of treatment weights (IPTW) to balance baseline characteristics and Fine-Gray models to estimate subdistribution hazard ratios (sHRs) accounting for competing risks of death and kidney transplantation. We estimated intention-to-treat and as-treated effects. RESULTS We identified 3,619 GLP-1 users and 11,502 DPP-4 users. After IPTW, the average individual was 63 years old, 63% were White, and mean BMI was 31 kg/m2. The median (interquartile interval) follow-up was 1.5 (0.6–2.9) years, and 2,014 patients received a dementia diagnosis. In the intention-to-treat analysis, the IPTW-sHR for dementia was 0.82 (95% CI 0.67–0.98), and after 2 years of follow-up, the cumulative incidence of dementia was 10.2% on GLP-1s vs 11.2% on DPP-4s. As-treated and subgroup analyses were consistent. GLP-1s were also associated with an increased risk of ketoacidosis (sHR 1.52, 95% CI 1.14–2.02; 2-year cumulative incidence: 3.1% vs. 2.2%). CONCLUSIONS In patients with diabetes requiring hemodialysis, GLP-1s (vs. DPP-4s) may be a promising therapy to reduce the risk of dementia.
胰高血糖素样肽1激动剂（glp -1）与二肽基肽酶4抑制剂（dpp -4）相比，与一般糖尿病患者痴呆风险降低相关，但这种关联是否适用于需要血液透析的患者尚不清楚。研究设计和方法使用2011年至2021年美国肾脏数据系统和医疗保险A、B和D部分索赔数据，我们使用主动比较器，新用户设计来评估糖尿病和血液透析依赖患者中glp -1与dpp -4的痴呆发生率。我们使用治疗权重逆概率（IPTW）来平衡基线特征，并使用Fine-Gray模型来估计考虑死亡和肾移植竞争风险的亚分布风险比（sHRs）。我们估计了意向治疗和已治疗效果。结果：我们确定了3619名GLP-1使用者和11,502名DPP-4使用者。IPTW后，平均年龄63岁，63%为白人，平均BMI为31 kg/m2。中位（四分位数间隔）随访时间为1.5（0.6-2.9）年，2014名患者被诊断为痴呆。在意向治疗分析中，痴呆的IPTW-sHR为0.82 (95% CI 0.67-0.98)，随访2年后，glp -1组的累计痴呆发病率为10.2%，而dpp -4组为11.2%。治疗组和亚组分析结果一致。glp -1也与酮症酸中毒风险增加相关（sHR 1.52, 95% CI 1.14-2.02； 2年累积发病率：3.1%对2.2%）。结论：在需要血液透析的糖尿病患者中，glp -1（与dpp -4相比）可能是一种有希望降低痴呆风险的治疗方法。
{"title":"GLP-1s Versus DPP-4s and Risk of Dementia in Patients Requiring Hemodialysis: A Target Trial Emulation Study","authors":"Dustin Le, Mark Kilpatrick, Walter K. Kraft, Morgan E. Grams, Bernard G. Jaar, Jung-Im Shin","doi":"10.2337/dc25-1836","DOIUrl":"https://doi.org/10.2337/dc25-1836","url":null,"abstract":"OBJECTIVE Glucagon-like peptide 1 agonists (GLP-1s) compared with dipeptidyl peptidase 4 inhibitors (DPP-4s) are associated with reduced risk of dementia in the general population with diabetes, but whether this association is true for patients requiring hemodialysis is unknown. RESEARCH DESIGN AND METHODS Using the U.S. Renal Data System and Medicare Parts A, B, and D claims data from 2011 to 2021, we used the active comparator, new-user design to evaluate incident dementia comparing GLP-1s versus DPP-4s among individuals with both diabetes and hemodialysis dependence. We used inverse probability of treatment weights (IPTW) to balance baseline characteristics and Fine-Gray models to estimate subdistribution hazard ratios (sHRs) accounting for competing risks of death and kidney transplantation. We estimated intention-to-treat and as-treated effects. RESULTS We identified 3,619 GLP-1 users and 11,502 DPP-4 users. After IPTW, the average individual was 63 years old, 63% were White, and mean BMI was 31 kg/m2. The median (interquartile interval) follow-up was 1.5 (0.6–2.9) years, and 2,014 patients received a dementia diagnosis. In the intention-to-treat analysis, the IPTW-sHR for dementia was 0.82 (95% CI 0.67–0.98), and after 2 years of follow-up, the cumulative incidence of dementia was 10.2% on GLP-1s vs 11.2% on DPP-4s. As-treated and subgroup analyses were consistent. GLP-1s were also associated with an increased risk of ketoacidosis (sHR 1.52, 95% CI 1.14–2.02; 2-year cumulative incidence: 3.1% vs. 2.2%). CONCLUSIONS In patients with diabetes requiring hemodialysis, GLP-1s (vs. DPP-4s) may be a promising therapy to reduce the risk of dementia.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"25 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher S. Wilson, Alexander Falk, Jonathan M. Williams, Melissa Hilmes, Jordan Ross, Lauren LeStourgeon, Michael J. Haller, Martina Drawdy, Joseph Pechacek, Taura Webb, Alicia Diaz-Thomas, William E. Russell, Justin M. Gregory, Jack Virostko, Michail S. Lionakis, Daniel J. Moore
OBJECTIVE Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic autoimmune disorder that may manifest as type 1 diabetes (T1D). Teplizumab, an anti-CD3 monoclonal antibody, delays progression of stage 2 T1D, but its effects in APS-1–associated diabetes are unknown. RESEARCH DESIGN AND METHODS We report clinical responses of two adolescents with APS-1 and stage 2 T1D who received 14-day courses of teplizumab. In one patient, pancreatic MRI and spectral immune cell phenotyping were performed before and after treatment. RESULTS Both patients exhibited improved glycemia. One who briefly required insulin recovered insulin independence 2 weeks after therapy. Pancreatic volume transiently increased, and circulating lymphocytes showed changes in homing receptors and senescence markers in the individual who underwent those studies. Nonpancreatic APS-1 manifestations were unchanged. CONCLUSIONS Teplizumab may preserve β-cell function in APS-1–associated T1D. Larger studies are needed to define efficacy, durability, and immunologic and tissue mechanisms in this rare context.
{"title":"Use of Teplizumab to Modulate Stage 2 Type 1 Diabetes in Two Individuals With Autoimmune Polyendocrine Syndrome 1","authors":"Christopher S. Wilson, Alexander Falk, Jonathan M. Williams, Melissa Hilmes, Jordan Ross, Lauren LeStourgeon, Michael J. Haller, Martina Drawdy, Joseph Pechacek, Taura Webb, Alicia Diaz-Thomas, William E. Russell, Justin M. Gregory, Jack Virostko, Michail S. Lionakis, Daniel J. Moore","doi":"10.2337/dc25-1444","DOIUrl":"https://doi.org/10.2337/dc25-1444","url":null,"abstract":"OBJECTIVE Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic autoimmune disorder that may manifest as type 1 diabetes (T1D). Teplizumab, an anti-CD3 monoclonal antibody, delays progression of stage 2 T1D, but its effects in APS-1–associated diabetes are unknown. RESEARCH DESIGN AND METHODS We report clinical responses of two adolescents with APS-1 and stage 2 T1D who received 14-day courses of teplizumab. In one patient, pancreatic MRI and spectral immune cell phenotyping were performed before and after treatment. RESULTS Both patients exhibited improved glycemia. One who briefly required insulin recovered insulin independence 2 weeks after therapy. Pancreatic volume transiently increased, and circulating lymphocytes showed changes in homing receptors and senescence markers in the individual who underwent those studies. Nonpancreatic APS-1 manifestations were unchanged. CONCLUSIONS Teplizumab may preserve β-cell function in APS-1–associated T1D. Larger studies are needed to define efficacy, durability, and immunologic and tissue mechanisms in this rare context.","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":"175 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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